JP2008163038A - Oral antimicrobial pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug useful for the treatment of infections of the large intestine, in particular the colon. <P>SOLUTION: The oral pharmaceutical composition is a controlled and/or delayed release oral pharmaceutical composition containing one or more than one kind of pharmaceutically acceptable excipients and metronidazole. The controlled and/or delayed releasabilty is formed by (a) an amphiphilic matrix taking in the metronidazole and (b) a substance having a melting point of lower than 90°C and given by more than one matrix structure including a lipophylic matrix with (a) dispersed in it and (c) a hydrophilic matrix. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an oral antimicrobial pharmaceutical composition.

  Intestinal infections are common diseases caused by colonization in the intestine by foreign pathogens of various origins or caused by enteric microorganisms that are normally present and toxic.

  The intestine is formed by two different parts: a proximal part called the “small intestine” formed by the duodenum, jejunum and ileum, in the head and tail direction, and the colon and recto-anus “ It is known to be divided into a distal part called “large intestine” (Non-patent Document 1).

  The two parts of the small and large intestines are separated anatomically completely by a ileocecal valve that allows the passage of intestinal contents from the small intestine to the large intestine but not from the large intestine to the small intestine .

  In addition to an anatomical structure, the large intestine is significantly different from the small intestine, especially from a functional viewpoint (Non-Patent Document 2).

  The small intestine is responsible for the digestion of most of the food, its absorption, the production of vitamins B and K, the metabolism of bile acids and various other organic substances, and the rapid transport of bolus to downstream sites However, the large intestine is responsible for the absorption of water, digestion of plant fibers and the completion of several digestive processes initiated in the small intestine.

  In addition, the large intestine is a fairly abundant bacterial flora (its balance is the regulation of ambient pH, motility, gas and ammonia production, stool formation, and the production of metabolites that are essential to maintaining good functioning of the large intestine. It is fundamentally important in the small intestine.

  Many of these differences between the small and large intestines explain the unique properties of several medical conditions that occur at the expense of the large intestine, particularly the colon.

  The colon is part of the large intestine, the host for most bacterial strains, and is particularly suitable for potentially toxic permanent flora or for the growth and colonization of pathogens Gives conditions for pH, anaerobic life, humidity and slow movement. For these reasons, the colon is the most susceptible area of the intestine. In fact, infection at the colon location (infectious colitis, bacterial dysentery, diarrhea, pseudomembranous colitis, diverticulitis, etc.) constitutes an important and unique chapter in gastroenterology research papers (non- Patent Document 3).

  Furthermore, increased intraluminal pressure associated with gas production and associated with a local predisposition is susceptible to infection and inflammation, and may promote the development of diverticula located exclusively in the colon (Non-Patent Document 4).

  Currently, oral treatment of intestinal infections, especially colon infections, is a substance with antibacterial activity and has unique properties, such as a broad activity spectrum for gram positive and gram negative bacteria, a strong acidic environment such as the stomach environment Used should have resistance to, infectious activity independent of the presence of intestinal biomass, retention in the gut for an appropriate period of time, good permeability to infected host cells and good tolerance (Non-patent document 5).

  There are at least two limitations to treatment with antimicrobial agents administered in oral formulations used today. First, antibacterial agents, if not properly protected, may lose efficacy due to inactivation by enzymes or degradation that occurs as they pass through the stomach or small intestine.

  Furthermore, the dosage forms used today allow administration of the active ingredient in individual doses, but the release of the active ingredient is too rapid for the time taken to pass through the digestive tract, resulting in The active ingredient provides anti-infectious activity indiscriminately throughout the digestive tract.

  This leads to the disappearance of non-pathogenic bacterial flora that grows in the small intestine (duodenum, jejunum and ileum), but the flora is usually not present at the site of infection and should be protected and used today It should not be exposed to the specific sterilization effects of the formulation.

  This is because, for example, the digestion and absorption of dietary nutritive components, the production and absorption of vitamins (vitamins K and B), the metabolism of bile acids and steroid hormones, the activity of various substances This is because it is known to be important for basic biological processes such as activation and inactivation and protection of living bodies from xenobiotics (Non-patent Document 5).

  In particular, normal oral antibacterial therapy for the treatment of medical conditions located in the colon often gives incompatible results, possibly due to excessive dilution of the active ingredient in the intestinal lumen. That is, this dilution is caused by an early release of the antimicrobial agent from a dosage form containing the antimicrobial agent, but this release occurs as early as in the stomach and in the immediate vicinity of the patient's pyloric valve.

  Furthermore, although antibacterial agents used to sterilize the gastrointestinal tract often do not have a high metabolic rate to keep the therapeutic potential associated with the administration of traditional dosage forms containing antibacterial agents unchanged In order to avoid any decrease in the effectiveness of the treatment associated with the presence of antimicrobial agents, the phenomenon of hypometabolism should not occur.

  Therefore, in such a case, it appears that there is a need for the feasibility of controlled and site-specific dosage forms to ensure the actual efficacy of anti-infection therapy.

  Because releasing antimicrobial / anti-infective active ingredients in the immediate vicinity of the diverticulum or the area where general infection is established will result in a much higher concentration gradient than in the conventional oral dosage form. This is because, as a result, the possibility that the antibacterial agent successfully penetrates into the diverticulum is increased.

  Under this circumstance, there is not a widespread but not only the possibility of alleviating socio-epidemiologically important infectious pathologies such as bacterial dysentery and pseudomembranous colitis, and the sacrifice of the large intestine, especially the colon. Particular emphasis is also placed on the possibility of reducing infectious complications in the surgical procedure.

  Rifamycin SV, known since the 1960s, is a semi-synthetic active ingredient that is derived from rifamycin S and has potent antibacterial and / or antiinfective activity locally and parenterally. is there. Its activity is also at the lowest concentration (mcg / ml) for Gram-positive bacteria such as Staphylococcus aureus or Enterococcus faecalis, and for Gram-negative bacteria such as Escherichia coli, Salmonella, Enterobacter aerogenes, Enterobacter cloacae or Pseudomonas aeruginosa In contrast, it was evaluated in vitro at relatively high concentrations.

  Rifamycin SV in the form of its sodium salt is currently sold under the name Rifocin® for both topical topical use and for injection. In particular, the topical use required for local treatment of the infectious process is limited to external use with a solution of the active ingredient, which should be diluted at the time of use.

  The patent application (US Pat. No. 5,697,097), incorporated herein by reference, describes the preparation of a pharmaceutical composition that can be used for the treatment of pathologies caused by abnormal bacterial growth at the expense of the small intestine (Small Intestin Overgrowth SIBO). For the use of antibacterial agents, including generic rifamycin. These compositions are formulated in such a way as to release the active ingredient rapidly in the proximal part of the intestine, ie exclusively in the small intestine (duodenum, jejunum and ileum).

  Metronidazole is a nitroimidazole chemotherapeutic drug with potent antibacterial activity and broad spectrum of activity against both gram positive and gram negative bacteria. Furthermore, it is known that metronidazole has verified antiprotozoal activity (Non-patent Document 6). Recent treatment with metronidazole is assisted by tablets (Flagyl®) containing 250 mg of active ingredient and formulated for immediate release.

WO 01/11077 EP 1183014 GB 2245492 EP 572942 Faller A, Scevola G. Anatomia e Fisiologia del Corpo Umano (Anatomy and Physiology of the Human Body). Vol I. Edizioni Minerva Medica, Turin, 1973, pp. 235-254 Braga PC.Enteric microflora and its regulation.In Drugs in Gastroenterology.Raven Press, New York, 1991, pp. 501-508 Sorice F., Vullo V. Intossicazioni alimentari e infezioni del tubo digerente. (Food Poisoning and Infections of the Alimentary Canal). In: Medicina Clinica (Clinical Medicine). Edizioni Medico Scientifiche, Turin, 2002 Jackson BT. Diverticular disease. In: Inflammatory Bowel Diseases Churchill Livingston, New York, 1997, pp. 443-447 Braga PC. Interaction of antibiotics on enteric microflora. In: Drugs in Gastroenterology. Raven Press, New York, 1991, pp. 509-517 Tracy J.W. et al., Metronidazole, in: Goodmen & Gilman's, The Pharmacological Bases of Therapeutics, IX Ed., 1996, pp 995-998

  Surprisingly, the efficacy of antibacterial / anti-infective active ingredients such as rifamycin SV and / or metronidazole in the treatment of infection of the large intestine, especially the colon, is active in the first part of the gastrointestinal tract, such as the stomach, duodenum and jejunum Metabolizes active ingredients that are brought about by removing the above undesirable effects caused by early release of ingredients (vitamin deficiency, degradation of non-pathogenic flora, etc.) and before the active ingredient can reach the site of infection It has been found that protecting against inactivation by sex enzymes can substantially increase.

  In particular, the efficacy of rifamycin SV is against certain pathogenic bacterial strains, such as Escherichia coli, Enterobacter faecalis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi and Enterobacter cloacae as shown in Table A below. This was confirmed by evaluation of MIC (Minimum Inhibiting Concentration).

  Accordingly, the present invention is an oral pharmaceutical composition containing an active ingredient having antibacterial / anti-infective action, such as rifamycin SV and / or metronidazole, which composition requires a specific sterilizing action The present invention relates to a composition characterized in that it is formulated in such a way as to substantially release the active ingredient in the large intestine part but not to alter the non-pathogenic bacterial flora present in the small intestine part that is not affected by infection.

  In particular, the formulations according to the invention are able to release the active ingredient exclusively in the colon, thus ensuring a local and limited anti-infective efficacy.

  As a result, the advantages of the formulations of the present invention are significant site specificity in the large intestine, especially the colon, allowing higher concentrations of active ingredients in the infected distal intestinal region and a healthy proximal Area protection is complete.

  This benefit is due to certain pathological conditions within the colonic region, such as infectious colitis, bacterial dysentery, diverticular disease and diverticulitis, where the site specificity and tolerability of the formulation play an important role in the resolution of the pathology Demonstrated mainly during treatment.

  A further advantageous application of the formulations according to the invention is the use of ammonia preparations for colonic surgery in the preparation of colonic surgery in the ileocolic anastomosis and for the prevention and / or treatment of hyperammonaemias. For use in sterilization. In these last-mentioned cases, the site specificity of treatment and the resulting active concentration of the active ingredient can be an important solution for cases that would otherwise involve substantial complications.

  In the preparation of the present invention, the substance having antibacterial / antiinfective activity is contained in an amount of 10 to 90% by weight, and particularly rifamycin SV is contained in an amount of 20% to 60% by weight. On the other hand, metronidazole is contained in an amount of 25% to 70% by weight.

The oral formulation of the present invention is selected from tablets, capsules, granules and / or fine granules.
Preferred embodiments of the invention include a controlled release system characterized by the presence of a first amphiphilic matrix incorporating an active ingredient and the matrix being dispersed in a second lipophilic matrix. . The dosage form thus obtained is dispersed again and further in the third hydrophilic matrix before producing the final oral dosage form.

  The lipophilic matrix of the present invention is represented by materials having a melting point of less than 90 ° C., such as beeswax, carnauba wax, stearic acid, stearin and the like. The amphiphilic matrix is represented by a material selected from, for example, phospholipids, ceramides, sphingomyelin, lecithin, alkyl block copolymers, sulfated alkyl acid salts, polyoxyethylenated alkyls, sorbitan derivatives, and the like, and The hydrophilic matrix is generally cross-linked or linear polymer or copolymer material known as hydrogel, i.e., due to the polar groups present in the polymer backbone or side chain when in contact with water molecules, the volume and Represented by substances that can increase weight.

  In particular, the hydrophilic matrix is, for example, a cellulose derivative such as hydroxyalkylcellulose, alkylcellulose, carboxyalkylcellulose and salts or derivatives thereof, polyvinyl alcohol, carboxyvinyl derivatives, anionic or cationic polysaccharide derivatives such as It corresponds to a substance selected from hyduronic acid, glucuronic acid, glucosamine, pectin and / or derivatives thereof.

  In this preferred embodiment, the matrix is dispersed with the active ingredient in succession to each other, thus resulting in a uniform structure formation that is responsible for the site specificity of release.

  Furthermore, in an embodiment of the invention, the tablets obtained are finally subjected to a coating process using gastroresistant substances, for example acrylic and methacrylic acid polymers (Eudragit) and / or derivatives of cellulose phthalate.

  Controlled and / or programmed release systems suitable for the present invention are described in US Pat. Nos. 5,047,028, 3,4, and 4, and are also incorporated herein by reference. Incorporated.

  The following examples illustrate the invention in detail without limiting the content of the invention in any way.

Example 1
200 g rifamycin SV is mixed with 5 g stearic acid, 7 g carnauba wax, 8 g sodium dioctylsulfosuccinate, 100 g lactose and 10 g sodium edetate and 25 g in 0.2 liters of purified water Was granulated with a solution containing a low-viscosity polyvinylpyrrolidone. Once the granulate was dried, it was mixed with 100 g sodium carboxymethylcellulose, 25 g silica, 5 g glycerol palmitostearate and 10 mg talc and then compressed to a unit weight of 495 mg / tablet. The core thus obtained is then film coated with an aqueous alcoholic dispersion of acrylic and methacrylic esters, titanium dioxide, talc and triethyl citrate to give the product a powerful mimicry of the stomach and small intestine environment. Resistant to degradation in acidic environment. The solubility of the tablets was essentially zero at pH conditions below 7, and proceeded in pH 7.2 intestinal buffer with the following percentage allocation:
Less than 20% after 1 hour dwell
Less than 50% after 3 hours residence
Over 70% after 8 hours dwell.

Example 2
Mix 500 g rifamycin SV with 10 g stearic acid, 10 g beeswax, 10 g sodium lauryl sulfate, 200 g mannitol and 10 g sodium edetate, 50 g hydroxy in 0.5 liter water Granulated with a solution containing propylcellulose. Once the granulate was dried, it was mixed with 150 g sodium hydroxypropylmethylcellulose, 25 g silica, 5 g glycerol palmitostearate and 10 mg talc and then compressed to a unit weight of 490 mg / tablet. The core thus obtained is then film coated with an aqueous dispersion of acrylic and methacrylic acid esters, iron oxide, talc and triethyl citrate to give the product a powerful mimicry of the stomach and small intestine environment. Resistant to degradation in acidic environment. The solubility of the tablets was essentially zero at pH conditions below 7, and proceeded in pH 7.2 intestinal buffer with the following percentage allocation:
Less than 30% after 1 hour dwell
Less than 60% after 3 hours residence
Over 80% after 8 hours dwell.

Example 3
Mix 2.5 kg of metronidazole with 70 g of stearic acid, 70 g of beeswax, 400 g of saccharose, 140 g of hydroxypropylmethylcellulose and 20 g of polysorbate and add purified water to the appropriate consistency. Granulated. The granulate was then dried and dimensioned, after which 200 g hydroxymethylpropylcellulose, 600 g microcrystalline cellulose, 30 g glycerol palmitostearate and 70 g silicon dioxide were added. After mixing, the powder was compressed to a unit weight of 450 mg / tablet.

The resulting core was then film coated with an aqueous alcohol dispersion of acrylic and methacrylic esters, iron oxide, talc and triethyl citrate to give the product resistance to degradation in an acidic environment. The solubility of the tablets was essentially zero at pH conditions below 7, and proceeded in pH 7.2 intestinal buffer with the following percentage allocation:
Less than 25% when staying within 1 hour,
Over 25% and less than 70% for stays within 3 hours
Over 80% after 8 hours dwell.

Example 4
Ingredients of 500 g metronidazole, lipophilic / amphiphilic matrix, 5 g stearic acid and 5 g soy lecithin, several hydrophilic polymers, 100 g hydroxypropylcellulose, and diluent, 150 g mannitol Mixed with.

  The mixture was then pasted with a low viscosity hydroxypropylcellulose solution of purified water until an even granule was obtained. After drying, the resulting granulate is further mixed with 100 g of hydroxypropylcellulose, to which is added a flow agent and lubricant, 5 g silica, 5 g talc and 5 g magnesium stearate, then Compressed to a final weight of 925 mg / tablet. The tablets were finally coated with an alcohol-based suspension of acrylic and methacrylic acid copolymers that can provide effective gastric tolerance to the tablets.

  The dissolution rate of these tablets is progressive and controlled, with approximately 20% of the active ingredient released after 1 hour residence in pH 7.2 intestinal fluid and 50% exceeding 80% after 2 hours. Are released after 4 hours, but these numbers clearly reflect the quota after 2 hours exposure at pH 1 and 1 hour exposure at pH 6.4, reflecting the gastric and small intestine environments, respectively. Is done.

Claims (14)

A controlled and / or delayed release oral pharmaceutical composition comprising metronidazole together with one or more pharmaceutically acceptable excipients, comprising:
Controlled and / or delayed release,
a) an amphiphilic matrix in which metronidazole is incorporated;
b) a lipophilic matrix formed of a material having a melting point of less than 90 ° C., in which a) is dispersed;
c) hydrophilic matrix,
An oral pharmaceutical composition characterized in that it is provided in a plurality of matrix structures.   The pharmaceutical composition according to claim 1, characterized in that the release of metronidazole occurs in the large intestine.   The pharmaceutical composition according to claim 1, characterized in that the release of metronidazole occurs in the colon.   4. The pharmaceutical composition according to claim 1, wherein metronidazole is contained in an amount of 10 to 90% by weight.   The pharmaceutical composition according to claims 1 to 4, characterized in that metronidazole is contained in an amount of 25 to 70% by weight.   The amphiphilic matrix is selected from lecithin, polyoxyethylenated sorbitan monooleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. To 5. The pharmaceutical composition according to 5.   Pharmaceutical composition according to claims 1 to 6, characterized in that the lipophilic matrix is selected from stearic acid, beeswax, carnauba wax, palmitic acid and / or palmitostearate ester.   Characterized in that the hydrophilic matrix is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, vinyl polymer, alginic acid and its salts and / or polysaccharide polymers, The pharmaceutical composition according to claims 1 to 7.   9. A pharmaceutical composition according to claims 1 to 8, characterized in that it comprises a protective coating on the stomach.   10. Pharmaceutical composition according to claims 1 to 9, characterized in that the protective coating in the stomach is selected from acrylic acid and methacrylic acid esters and / or cellulose acetate phthalate.   11. The pharmaceutical composition according to claim 1 for treating a medical condition of the large intestine.   11. A pharmaceutical composition according to claims 1 to 10 for the treatment of colon pathologies.   13. A pharmaceutical composition according to claims 1 to 12, for treating infectious colitis, bacterial dysentery, pseudomembranous colitis, traveler's diarrhoea, diverticular disease and / or diverticulitis.   14. Pharmaceutical composition according to claims 1 to 13 for pretreatment for colon surgery and / or adjunct therapy in the treatment of ammonaemias or hyperammonaemias.